The value of prick tests in the detection of anaphylaxis caused by muscle relaxants

Intradermal tests (IDR) are a sure diagnostic procedure for confirming the IgE origin of anaphylactoid accidents due to muscle relaxant drugs. Because carrying these out and interpreting them correctly is difficult, epidermal prick-tests (PT) could be used if they proved as sure as IDR. To ascertain this, IDR and PT were carried out in 38 patients who had a shock after being given a muscle relaxant 6 months to 5 years previously; for these tests, increasing concentrations of five muscle relaxants were used (suxamethonium, gallamine, alcuronium, pancuronium and vecuronium). The PT were also carried out with the five same pure and diluted muscle relaxants in a group of 147 volunteer controls. For the 38 patients, PT and IDR were always positive for the same drugs, but at different concentrations, the epiderm seeming less sensitive than the derm (with a ratio of 1 to 100). In the control group, all the tests were negative, even with the pure drug. PT with muscle relaxants were sensitive, specific of anaphylaxis, and permanent. Easy to carry out, easily interpreted, they could be useful as tests for predicting latent sensitisation in risk patients requiring muscle relaxants. But all muscle relaxants must be tested, and not just the one the anaesthetist is likely to use.     

The role of muscle relaxants in total intravenous anaesthesia

For total intravenous anaesthesia (TIVA), all drugs that are required as part of the anaesthetic method are administered intravenously. This is usually taken to imply the use of intravenous infusions. It is normal practice to administer muscle relaxants intravenously, although other routes have been used. A muscle relaxant is required firstly to secure paralysis and secondly to maintain paralysis. The rate of onset of all the nondepolarizing neuromuscular blocking agents which are routinely available at present is similar; it takes about 3–6 min for a normal clinical dose to reach maximum effect. Maintenance of an adequate level of block is necessary, and it is usually helpful to the surgeon for the level of block to be relatively constant. The choice of drug is important. It should cause negligible side-effects. For administration by infusion, an agent with an intermediate (e. g., atracurium) or short (e. g., mivacurium) duration of action is essential to ensure a rapid recovery of effect on termination of the infusion. The routine use of neuromuscular monitoring is recommended when a continuous infusion of a relaxant is used.     

Reexamined: the recommended endotracheal intubating dose for nondepolarizing neuromuscular blockers of rapid onset

The results of any study of the relative importance of anesthetic depth versus intensity of neuromuscular block on conditions for endotracheal intubation can be manipulated by the investigator. Several independent factors, such as the depth of hypnosis induced, the interval between drug administration and laryngoscopy, the onset profile of the muscle relaxant, and the multiple of the 95% effective dose given, must be controlled. We attempted to design an induction sequence that provided good to excellent conditions for laryngoscopy and endotracheal intubation within 75-90 s of muscle relaxant administration with doses smaller than often suggested, while still administering only customary amounts of hypnotics and opioids. Alfentanil 12.5 microg/kg, propofol 2.0 mg/kg, and a test drug were administered rapidly. The test drugs were saline 0.05 mL/kg (n = 10), rapacuronium 1.0 or 1.2 mg/kg, or rocuronium 0.50 mg/kg (n = 30 each). Laryngoscopy was commenced 75 s after the test drug. Clinically acceptable conditions for intubation were achieved in all subjects after rocuronium or rapacuronium 1.2 mg/kg and in 28 of 30 patients after rapacuronium 1.0 mg/kg. In the Saline group, only 3 individuals achieved a good or excellent rating, and intubation was impossible in 2 of 10 individuals. For muscle relaxants of low potency, doses only 1.5 times the 95% effective dose can provide very satisfactory conditions for intubation if laryngoscopy is delayed to 75 s after drug administration. IMPLICATIONS: The dose of muscle relaxant usually recommended for facilitating tracheal intubation approximates at least two times the drug's effective dose (ED(95)). When the muscle relaxant in question has a rapid onset of action, this intubation dose may be decreased to 1.5 times the ED(95).     

Subsequent general anaesthesia in patients with a history of previous anaphylactoid/anaphylactic reaction to muscle relaxant

Of 151 patients with a possible anaphylactoid/anaphylactic reaction to a muscle relaxant investigated over a 20-year period, follow-up for any subsequent general anaesthesia was complete in 145 (96%). One hundred and twenty-two anaesthetics in 72 patients were documented. There were no anaesthetic-related deaths. No subsequent reactions were seen if muscle relaxants were not used in the subsequent anaesthetic, nor were they in patients with severe reactions if the original intradermal test had been equivocal or negative. In the patients with a severe reaction and a positive intradermal test to one or more muscle relaxants, six out of 40 later anaesthetics using muscle relaxants were associated with clinical problems, three being probable anaphylactic reactions, whilst three were minor. Intradermal testing should be performed prior to surgery in this group of patients for the muscle relaxant(s) planned, or an anaesthetic technique which avoids relaxants should be used. This review should encourage other centres to undertake similar follow-up.     

Anesthetic management of two patients with polymyositis

We report anesthetic experience of two patients suffering from polymyositis. The first case is a 56 year old woman who underwent tympanoplasty for cholesteatoma of the middle ear. Anesthesia was induced with thiopental and deepened with oxygen-nitrous oxide and sevoflurane. No muscle relaxant was used for endotracheal intubation and for maintaining anesthesia. Another is a 61 year old man who underwent open reduction and internal fixation for condyle fracture of the tibia. Epidural catheter was inserted at L 3-L 4. Epidural blockade was established with 2% mepivacaine, and sedation was achieved by intravenous midazolam. Concerning the anesthetic management of a patient with polymyositis, there are some informations on the appropriate use of muscle relaxants. It is generally believed that the patient is sensitive to nondepolarizing muscle relaxants and the use of antagonist drug (reversal) may cause muscle weakness, severe dysrhythmia, et al. Therefore we think it is appropriate to manage such a patient without muscle relaxants.     

Muscle relaxants: past,present and future

Muscle relaxants are an irreplaceable item within the modern surgical toolkit. Their almost universal use during surgical procedures of medium-to-long duration means that it is essential that all anaesthetists must have a comprehensive knowledge of their history and the future prospects for their continued evolution. In the context of identifying the ‘ideal’ muscle relaxant, this review focuses on those areas of muscle relaxant action that are either highly desirable or highly undesirable—and discusses the extent to which any identified problems have, or have not, been overcome with the existing range of clinically available muscle relaxant compounds. Pharmacodynamic topics covered include the actions of muscle relaxants on the range of different subtypes of nicotinic acetylcholine receptors, the actions of muscle relaxants on motor nerve terminals and the major non-neuromuscular actions of muscle relaxants. From a pharmacokinetic perspective, how the pharmacological and chemical properties of muscle relaxants influence the clinical properties and uses of the compounds are discussed.     

Prospective preoperative survey of 300 patients using prick tests with muscle relaxants

It is now well established that the retrospective diagnosis of anaphylaxis to muscle relaxants may be based on skin prick testing. These tests, which use undiluted solutions of muscle relaxants, are as sensitive, specific and reproducible as intradermal tests for the diagnosis of IgE related adverse reactions to muscle relaxants. The rate of muscle relaxant anaphylaxis (1/1 500 to 1/5 000) justifies its prevention based on a possible latent sensitization. A prospective investigation was carried out in 300 surgical patients scheduled for general anaesthesia. Prick tests were carried out using the 6 available muscle relaxants: suxamethonium, gallamine, alcuronium, pancuronium, vecuronium and atracurium. The wheal the drug might produce was compared with that obtained with codeine phosphate (a histamine releasing drug). Thirty-seven patients (13%) were considered to be atopic; 262 (87%) had undergone a previous anaesthesia. Three percent (n = 11) of tests were positive for atracurium. The wheal produced by atracurium was in favour of non-specific histamine release. One test was found positive for suxamethonium. Confirmation of this probable latent sensitization was unfortunately not possible. There were no other positive skin tests. Muscle relaxants were subsequently used in 58 patients (80% vecuronium) without any problem. Skin prick testing should be used on a larger scale to detect latent sensitization. However, predictive skin tests with atracurium should be avoided, as wheal reactions with this drug are probably due to non-specific histamine release.     

Acute quadriparesis in an asthmatic treated with atracurium

An 18-yr-old male asthmatic was paralyzed with atracurium for a period of seven days to facilitate mechanical pulmonary ventilation. After withdrawal of the muscle relaxant, train-of-four neuromuscular monitoring demonstrated rapid recovery of normal function. Three days later he developed acute quadriparesis without respiratory compromise. Electrophysiological studies showed normal conduction velocities, low compound muscle action potential amplitudes and evidence of denervation. Most cases of post-ventilatory weakness in the ICU involve the use of vecuronium and pancuronium. It has been suggested that the steroid nucleus in these muscle relaxants may be responsible. Our patient developed generalised weakness after treatment with atracurium, a benzylisoquinolinium muscle relaxant. Thus, it appears that the steroid nucleus of vecuronium and pancuronium is not essential in causing post-ventilatory weakness.     

Anaphylaxis to muscle relaxants. Predictive value of intradermal tests and study of crossed anaphylaxis

37 patients were studied, all of whom presented with anaphylaxis to a muscle relaxant. The diagnosis was made after simultaneous intradermal testing (IDT), human basophil degranulation tests (HBDT) and Prausnitz-Küstner tests (PK) of passive cutaneous anaphylaxis. Three tests were positive in 6 patients, both IDT and PK in 9, and both IDT and HBDT in 8. In 14 patients, the IDT, repeated twice, were positive both times. A search for crossed anaphylaxis to the other muscle relaxants was carried out in all the patients during a second series of tests, a few months to years after the first one. The drugs tested, at dilutions of the pharmaceutical preparation of 10(-3) or more, were: suxamethonium, gallamine, alcuronium, pancuronium, vecuronium, d-tubocurarine. The reliability of IDT in the diagnosis of anaphylaxis is discussed in terms of the small reactive concentration, the producibility of the tests, the one HBDT that did become positive later, and in one case the occurrence of shock by crossed anaphylaxis. Skin reactivity seemed to remain constant with time, so allowing the use of IDT as a diagnostic tool, in cases of old anaphylactoid shocks, occurring during general anaesthetics. The frequency of crossed anaphylaxis was assessed to be about 84%. The sensitivity to one or other drugs varied with each patient. Pancuronium and vecuronium appeared to be the least likely drugs to cause crossed anaphylaxis. The predictive use of these tests is discussed. It is also suggested that muscle relaxants with only one quaternary ammonium group should be used, this chemical characteristic probably reducing the risks of sensitization.     

Anaesthesia for Friedreich's ataxia. Case report

Friedreich's ataxia is an inherited neuromuscular disorder often associated with significant cardiac disease and requiring special care during anaesthesia because of increased sensitivity to muscle relaxants. We report a 37 years old female patient with Friedreich's ataxia who underwent anaesthesia for total hip replacement because of degenerative hip arthritis. Anaesthesia was induced with alfentanil and propofol. Endotracheal intubation was achieved without the use of any muscle relaxants and muscle relaxants were avoided throughout the operation. Anaesthesia was maintained with propofol infusion and intermittent bolus doses of alfentanil. At the end of the procedure recovery from anaesthesia was fast and uneventful. When there is no absolute indication for neuromuscular blocking agents as its the case for many orthopaedic operations, avoiding these drugs would simply avoid many potential complications due to muscle relaxant use in this group of patients.     

Muscle weakness after muscle relaxants: an audit of clinical practice

Residual muscle weakness after general anaesthesia, assessed using handgrip strength, was audited in a teaching hospital. The relationships between residual weakness, the use of muscle relaxants and patient characteristics were examined. Handgrip strength was measured preoperatively, one hour postoperatively and one day postoperatively using a hand dynamometer in 151 patients having general anaesthesia. Forty-nine patients received no muscle relaxant, 34 patients received vecuronium and 68 received rocuronium. Patients were managed by their anaesthetist according to that anaesthetist's clinical choice. All patients who received muscle relaxants received neostigmine. One hour postoperatively, there was a decline in handgrip strength of 16% for the no relaxant group, 24% for vecuronium and 29% for rocuronium. The degree of weakness for the relaxant groups was unrelated to age (P=0.89) but was strongly influenced by the patient's sex. Almost all of the increased weakness with relaxants was found in the female patients. The mean decline in handgrip strength in the male patients who received either vecuronium or rocuronium was similar to that seen when relaxants had not been used (P=0.40). One hour postoperatively, female patients showed a marked decrease in handgrip strength after both vecuronium and rocuronium (32% and 34% respectively, combined P=0.01). These results suggest that in usual clinical practice at our institution, female patients are more likely to have residual weakness after muscle relaxants.     

Skin testing in the investigation of reactions to intravenous anaesthetic drugs. A prospective trial of atracurium and tubocurarine

Intradermal skin testing is widely used to determine the causative drugs of presumed anaphylactic anaesthetic reactions. This paper sets out to evaluate the usefulness of skin tests, both intradermal and prick testing, in the prediction of anaesthetic reactions. The muscle relaxant drugs tubocurarine and atracurium were chosen for study since they are known to produce a high incidence of minor histaminoid reactions. A trial was conducted in 22 female patients about to undergo elective gynaecological surgery for non-malignant conditions. In intradermal tests, positive wheal and flare reactions to one or other relaxant (diluted 1 in 1,000) occurred in 17 patients and reactions to both drugs in 11 patients. Despite this high incidence of positive reactions, none of the patients had received either drug previously, a view confirmed by the negative results of prick testing. Likewise, when anaesthetized for surgery using atracurium or tubocurarine allocated randomly, the minor histaminoid manifestations observed showed no correlation whatsoever with the intradermal tests results. The results of the trial, combined with external reports to this centre, indicate that intradermal testing of anaesthetic drugs, particularly muscle relaxants, produces a high incidence of false positive results. This probably reflects their pharmacological activity rather than antigenicity. It is recommended, therefore, that skin testing should be reserved for situations in which there are strong indications from laboratory tests, backed by case history, of immune sensitization.     

Use of premedication for intubation in tertiary neonatal units in the United Kingdom

Background:  Endotracheal intubation and laryngoscopy are frequently performed procedures in neonatal intensive care. These procedures represent profoundly painful stimuli and have been associated with laryngospasm, bronchospasm, hemodynamic changes, raised intracranial pressure and an increased risk of intracranial hemorrhage. These adverse changes can cause significant neonatal morbidity but may be attenuated by the use of suitable premedication.
Aims:  To evaluate current practices for premedication use prior to elective intubation in UK tertiary neonatal units.
Methods:  Telephone questionnaire survey of all 50 tertiary neonatal units in the UK.
Results:  Ninety percent of units report the routine use of sedation prior to intubation and 82% of units routinely use a muscle relaxant. Morphine was the most commonly used sedative and suxamethonium was the most commonly used muscle relaxant. Approximately half of the units also used atropine during intubation. Seventy seven percent of units had a written policy for premedication. Ten percent of the units did not routinely use any sedatives or muscle relaxants for elective intubation.
Conclusions:  In comparison with data from a 1998 survey, our study demonstrated an increase in the number of units that have adopted a written policy for premedication use, and in the number routinely using premedication drugs for elective intubation. There remains little consensus as to which drugs should be used and in what dose.     

Awareness, muscle relaxants and balanced anaesthesia.

The incidence of awareness during insufficient anaesthesia is reported to be one per cent. It is usually due to the use of muscle relaxants, a balanced technique and the lightest possible depth of anaesthesia. Increased incidences were noted in open-heart surgery, during intubation-endoscopy procedures and in caesarean delivery patients. Experiences of awareness are disturbing to patients, who are usually benefited by a sympathetic and forthright explanation of the event. Fourteen representative cases of the problem are reported. Since no adequate sign or test exists for detection of awareness during very light anaesthesia or with associated paralysis, more meticulous attention is required in using relaxants or the balanced technique. Greater anaesthetic supplementation and reduction in the use of relaxants are recommended to halt the recurrence of this most serious anaesthetic problem.     

Reversal of neuromuscular blockade

Intelligent, safe use of muscle relaxants dictates that the clinician monitor neuromuscular function in all patients to determine each patient's sensitivity to relaxants. Restoration of muscle strength is a function of pharmacological antagonism of residual NMB, spontaneous recovery as the concentration of relaxant declines at the neuromuscular junction, or both. In addition to recovery of "normal function" by clinical and monitoring criteria, some margin of safety of neuromuscular function must be restored. As new relaxants with very short half-lives become available, it is likely that steady states of relaxation will increasingly be maintained with continuous infusions. In this setting, the rapid rate of spontaneous recovery of both clinical neuromuscular function and an adequate margin of safety may vastly reduce the need for pharmacological antagonism.     

Life-threatening anaphylactoid reactions to muscle relaxants

Sixty-seven patients who had life-threatening reactions to muscle relaxant drugs diagnosed by intradermal testing or challenge were studied. Six patients reacted on two occasions; four reacted to different relaxants. There was a significantly greater ratio of female-to-male patients who reacted than in a nonreacting population. Patients who reacted to muscle relaxants had an incidence of allergy, atopy, asthma, and previous reactions to anesthesia that was significantly greater than nonreacting patients, but not greater than patients who had reacted to induction agents. Eighty-five percent of patients who reacted to muscle relaxants had never previously been exposed to the drug, whereas 60% of patients reacting adversely to induction agents had been previously exposed to induction agents. The reactions were not related to additives or preservatives. In spite of a lack of previous exposure, type I hypersensitivity appears the most likely mechanism responsible for life-threatening reactions to muscle relaxants.     

In vitro diagnosis and studies on the mechanism(s) of anaphylactoid reactions to muscle relaxant drugs

By covalently coupling alcuronium, d-tubocurarine and the pancuronium analogue, vecuronium, and using the resultant complexes in radioimmunoassays with patients' sera, we have found high levels of drug-reactive IgE antibodies in some subjects who reacted to these muscle relaxants. This is the first demonstration of IgE antibodies to such compounds. Assays were also developed for the detection of drug-reactive IgE antibodies to the muscle relaxant drugs succinylcholine, decamethonium and gallamine. They involved the coupling of choline and its ethyl analogue, triethylcholine to activated Sepharose. Results of direct binding and inhibition experiments and correlations with clinical findings demonstrated that the assays are relevant to the detection of succinylcholine-, decamethonium- and gallamine-reactive IgE antibodies in patients who experienced adverse reactions to these drugs. Quantitative inhibition studies revealed that IgE antibodies from most patients cross-reacted with all muscle relaxants tested, other quaternary ammonium compounds and some pharmacologically unrelated drugs including promethazine, morphine, neostigmine and pentolinium. Results showed that the specificities of the IgE antibodies are directed towards quaternary or tertiary ammonium ions on the drugs that bind the antibodies. As these ions occur widely in man's environment in drugs, cosmetics, disinfectants, foods and industrial materials, it seems possible that sensitization of patients may occur without previous exposure to muscle relaxant drugs. Thus, we now have assays that will detect antibodies to all six muscle relaxant drugs --alcuronium, d-tubocurarine, pancuronium, succinylcholine, decamethonium and gallamine-- and, for the first time since the work on penicillins, drug-specific IgE antibodies have been found in large numbers of patients and the allergenic determinants have been identified.     

Anaphylactoid reactions after cisatracurium administration in six patients.

IMPLICATIONS: We report six cases of anaphylactoid reaction after the administration of the muscle relaxant cisatracurium. They include two first-time documented anaphylactoid reactions after a precurarising dose. These incidents challenge existing views of a substantially reduced anaphylactoid potential of cisatracurium relative to other muscle relaxants.     

A model for determining the influence of hepatic uptake of nondepolarizing muscle relaxants in the pig

Hepatic uptake and distribution of nondepolarizing muscle relaxants in pigs was investigated. A portocaval shunt preparation enabled the determination of the pharmacodynamics of nondepolarizing muscle relaxants both during temporary liver exclusion and intraportal injection in the same animal. To demonstrate the validity of the model in pigs, in a pilot study the influence of hepatic uptake on neuromuscular blockade by pancuronium (n = 3) and its congener Org 6368 (n = 3) was determined. Thereafter, the influence of hepatic uptake on neuromuscular blockade by gallamine (3.4 mg/kg, n = 5), Org 6368 (0.3 mg/kg, n = 5), and vecuronium (0.1 mg/kg, n = 4 and 0.15 mg/kg, n = 5) was studied in pigs anesthetized with pentobarbital. Each pig received one relaxant, which was injected four consecutive times under different conditions. The first injection was into the jugular vein (iv) the second into the portal vein, the third was iv while the liver was excluded for 10 min and the fourth was iv (control). After each injection the onset time, intensity, recovery rate, and total duration of neuromuscular blockade were measured. These variables were compared between the four injections for each relaxant. In the pilot study the influence of hepatic uptake on neuromuscular blockade was similar for pancuronium and Org 6368. For gallamine the onset time, intensity, recovery rate, and duration of action were similar after all four injections. For Org 6368 the variables of neuromuscular blockade were similar after iv and intraportal injection, but exclusion of the liver prolonged the neuromuscular block.(ABSTRACT TRUNCATED AT 250 WORDS)     

THE ROLE OF THE NON-DEPOLARIZING DRUGS IN THE PREVENTION OF SUXAMETHONIUM BRADYCARDIA

Evidence has been presented to show that a second dose of suxamethoniumis capable of producing a severe bradycardia in man. This responsemay be effectively prevented by the prior administration ofcertain non-depolarizing muscle relaxants namely tubocurarine,alcuronium, c-toxiferine and pancuronium in quantities of one-quarteror less of their muscle relaxant level. It is suggested thatsuxamethonium causes altered cardiac rhythm by stimulation ofafferent vagal receptors, which action may be blocked by tubocurarineand similar drugs. ^*Present address: Basingstoke and District Hospital.